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B Hoskins

Publications and source records attributed to B Hoskins.

At least 91 records · Page 5Linked to original sources
PubMed1984

Effect on striatal dopamine metabolism and differential motor behavioral tolerance following chronic cholinesterase inhibition with diisopropylfluorophosphate.

Rats were treated with diisopropylfluorophosphate (DFP), using 1 or 2 mg/kg acutely, or with 1 mg/kg daily for 4, 14 or 28 days. Their behaviors and striatal dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) levels were studied. The behaviors: tremors, chewing-movements and hind-limb abduction induced by DFP increased in a steeply dose-dependent manner. Chronic treatment for up to 28 days produced biphasic patterns of change for all the behavioral parameters. Tremor occurred in a complex spectrum of slow to intense fast types. Except for chewing, tolerance developed for these parameters, but at different rates. After acute treatment striatal DA and DOPAC levels were altered and the DOPAC/DA ratios were consistently increased within about the first two hr, suggesting an increased turnover of DA. After chronic treatment for 4 and 14 but not 28 days, both DA and DOPAC levels were decreased without a change in their ratios. It is suggested that the changes in DA metabolism arose secondarily to an elevation of brain acetylcholine following cholinesterase inhibition. A prolonged change in the levels or turnover of DA could be responsible for increase of postsynaptic DA receptor density previously found by us [36], which might then partly mediate the behavioral tolerance to DFP.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

An assessment of comparative acute toxicity of diisopropyl-fluorophosphate, tabun, sarin, and soman in relation to cholinergic and GABAergic enzyme activities in rats.

The sc LD50s (mumol/kg) in rats for diisopropylfluorophosphate (DFP), Tabun, Sarin, and Soman were 14.5, 1.9, 1.4, and 0.88, respectively. The relative potency was as follows: DFP less than Tabun less than Sarin less than Soman (1:7.6:10.4:16.4). The relative potencies correlated with the in vitro acetylcholinesterase (AChE) inhibition (in terms of the IC50) by these compounds, in whole brain homogenates or the purified bovine erythrocyte AChE. There was a dose versus time for mortality relationship for all four compounds; the average time for death decreased with increase in dose. However, there was no correlation between time for death and the extent of AChE inhibition. The striatal as well as other regional (medulla, diencephalon, cortex, and cerebellum) AChE activity was inhibited over 90% of the control, by the lethal doses of these compounds. None of the lethal or sublethal doses had any apparent effect on choline acetyltransferase (CAT) or GABA-transaminase activities. Glutamic acid decarboxylase activity was increased by Soman, Sarin, and Tabun at certain lethal doses but was not affected by DFP even at the lethal dose. The results indicate that (a) the acute toxicity of organophosphate acetylcholinesterase inhibitors is directly related to the inhibition of AChE though there is a wide difference in their potency; (b) a substantial inhibition of AChE activity (over 90% of control) is necessary for lethality to ensue after an acute exposure and the margins between lethal and nonlethal doses are extremely small; and (c) qualitative differences seem to exist among the various organophosphates in affecting noncholinergic neurotransmitter enzymes.

4-Aminobutyrate Transaminase↗
PubMed1984

Effects of diisopropylfluorophosphate (DFP) on renal function in the rat.

Numerous studies have suggested a role for the nervous system in renal function. Several cholinergic agents have been examined for effects in vivo and in renal slices. Effects mediated through the vascular system and also direct effects have been reported. In this study an irreversible cholinesterase inhibitor, diisopropylfluorophosphate (DFP) in doses of 1-4 mg/kg, was tested on renal function. A single dose of DFP (2, 3 or 4 mg/kg) caused an increased flow of urine of low osmolality over the 6 h after the administration of the drug with essentially a return to control status by 24 h after either of the lower doses. Twenty-four hours after 4 mg/kg, urine volume was less and urine osmolality greater than control. Renal and brain cholinesterases remained depressed 24 h after DFP. In acute experiments on anesthetized animals, inulin clearance was increased by the lower doses and decreased by the highest dose of DFP. Renal blood flow measured with an electromagnetic flow meter showed a similar dose-response relationship. However, urine flow increased at all doses. The increased urine flow associated with decreased inulin clearance (4 mg/kg) and renal blood flow (3 or 4 mg/kg) suggest a direct effect of DFP on renal tubular function. These effects do not appear to be related to inhibition of cholinesterase.

Animals↗
PubMed1984

Evidence for a direct action of insulin to increase renal reabsorption of calcium and for an irreversible defect in renal ability to conserve calcium due to prolonged absence of insulin.

Male rats were injected with streptozotocin (STZ), 60 mg/kg, i.p., on 2 successive days. Six hours after the last STZ injection, some STZ-diabetic rats began receiving daily injections of insulin that were insufficient to control blood glucose. Another group of STZ-diabetic rats received insulin injections after 2 wk duration of untreated diabetes. Still other STZ-diabetic rats received no insulin treatment. Under sodium pentobarbital anesthesia, kidneys from each treatment group were isolated and perfused with an artificial "plasma" containing 45Ca. As urine was collected, urine-to-perfusate ultrafiltrate (U/P) ratios for 45Ca were determined. The results of the studies showed that: STZ diabetes reduced 45Ca reabsorption by the kidney; the increased urinary excretion of calcium was not due to an osmotic effect or to a direct nephrotoxic action of STZ; and insulin therapy instituted early, but insufficient to control blood glucose, reduced the diabetes-induced calcium loss via a direct action on the kidney, whereas insulin therapy instituted late failed to reverse renal loss of calcium.

Animals↗
PubMed1983

Preoperative irradiation for unresectable rectal and rectosigmoid carcinomas.

The records of 25 patients with unresectable carcinoma of the rectum and rectosigmoid who received preoperative radiation therapy (RT) were reviewed. Twenty patients were considered to be resectable following RT (80%). Sixteen patients (64%) underwent curative resections. All patients with unresectable tumors following RT died with tumor within two and one half years (median survival, 11 months). For patients undergoing curative resection, the probability of two- and five-year survival was 56% and 43%, respectively. In this latter group, five of seven patients with treatment failures (71%) had a pelvic component of disease. The incidence of pelvic recurrence was correlated with the pathologic stage, extent of resection and preoperative radiation dose. The need for more aggressive treatment for patients with these advanced tumors is emphasized. Future treatment alternatives are discussed.

Aged↗
PubMed1983

Low-dose preoperative irradiation, surgery, and elective postoperative radiation therapy for resectable rectum and rectosigmoid carcinoma.

A regimen of low-dose preoperative radiation therapy (RT), surgery, and elective postoperative RT for resectable carcinomas of the rectum and rectosigmoid is presented. Initial results in a group of 36 patients is discussed. In four patients clinically silent metastatic disease was discovered. Of 16 patients without indications for postoperative RT, only one died with disease. Indications for postoperative irradiation were found in 15 patients and four relapses (26%) subsequently occurred. Since the surgicopathologic stage of the tumor is the best prognostic predictor for rectal cancer, this regimen allows for the delivery of high-dose adjuvant irradiation only to those at high risk of local recurrence. Thus, this combination selects patients likely to benefit from postoperative RT while preserving the advantages of preoperative RT.

Female↗
PubMed1983

Effect of acute and chronic cholinesterase inhibition with diisopropylfluorophosphate on muscarinic, dopamine, and GABA receptors of the rat striatum.

The effects of acute and chronic administration of diisopropylfluorophosphate (DFP) to rats on acetylcholinesterase (AChE) activity (in striatum, medulla, diencephalon, cortex, and medulla) and muscarinic, dopamine (DA), and gamma-aminobutyric acid (GABA) receptor characteristics (in striatum) were investigated. After a single injection of (acute exposure to) DFP, striatal region was found to have the highest degree of AChE inhibition. After daily DFP injections (chronic treatment), all brain regions had the same degree of AChE inhibition, which remained at a steady level despite the regression of the DFP-induced cholinergic overactivity. Acute administration of DFP increased the number of DA and GABA receptors without affecting the muscarinic receptor characteristics. Whereas chronic administration of DFP for either 4 or 14 days reduced the number of muscarinic sites without affecting their affinity, the DFP treatment caused increase in the number of DA and GABA receptors only after 14 days of treatment; however, the increase was considerably lower than that observed after the acute treatment. The in vitro addition of DFP to striatal membranes did not affect DA, GABA, or muscarinic receptors. The results indicate an involvement of GABAergic and dopaminergic systems in the actions of DFP. It is suggested that the GABAergic and dopaminergic involvement may be a part of a compensatory inhibitory process to counteract the excessive cholinergic activity produced by DFP.

Acetylcholinesterase↗
PubMed1983

Variation of commercial diisopropyl fluorophosphate preparations in toxicological studies.

The variation of three diisopropyl fluorophosphate (DFP) lots obtained from two sources was investigated. The effects of different lots of DFP on body weight, mortality, and brain acetylcholinesterase activity in rats varied significantly. The in vitro effects of these DFP preparations on brain acetylcholinesterase activity also were markedly different. It appears that different commercial preparations of DFP possess different potencies and that the same apparent doses of different DFP preparations will not produce the same effects upon any physiological system under study.

Acetylcholinesterase↗
PubMed1983

Calmodulin levels and divalent cation pump activities in kidneys of streptozotocin-diabetic rats.

Levels of calmodulin and activities of calcium and magnesium ATPases were determined in renal tissues of age-matched male rats after increasing durations of the following conditions: untreated streptozotocin (STZ) induced diabetes; STZ-diabetic rats which received daily insulin (NPH) treatment beginning 24 hours after STZ administration; and STZ-diabetic rats which began receiving NPH after having endured untreated diabetes for 1, 2, and 3 weeks. Results were compared with those of age-matched control animals. Calmodulin levels were the same in renal tissues from all groups of rats as were magnesium-ATPase activities. Calcium-ATPase activities were significantly higher than control activities after 2 weeks of untreated STZ-diabetes and in tissues from all rats that received insulin treatment which was instituted after 1, 2 and 3 weeks of STZ-diabetes. Calcium ATPase activities of tissues from rats which received insulin treatment 24 hrs after STZ injections were no different from control values. The data indicate that prolonged deficiency of insulin results in insufficient passive transport of calcium from urine into tubular cells. Thus, the increased activity of calcium-ATPase on the contraluminal membrane of kidney cells represents a futile attempt to conserve calcium.

Adenosine Triphosphatases↗
PubMed1983

Diisopropylfluorophosphate and GABA synaptic function: effect on levels, enzymes, release and uptake in the rat striatum.

The present study revealed that diisopropylfluorophosphate increased the GABA and glutamate levels, decreased the uptake of GABA, decreased the spontaneous release of GABA and did not exhibit its effects on the metabolic enzymes of GABA, glutamic acid decarboxylase and GABA-transaminase. These results, together with our previous finding that the postsynaptic GABA receptor population is increased by DFP treatment, indicate that GABA transmission is affected by DFP. An overall enhancement of GABA function appears to be involved in DFP poisoning; it is suggested that this may be a compensatory mechanism to counteract the cholinergic hyperactivity.

4-Aminobutyrate Transaminase↗
PubMed1983

Assessment of diisopropylfluorophosphate (DFP) toxicity and tolerance in rats.

Single s.c. injection of 1, 2, 3 or 4 mg/kg of DFP in saline was given to male rats. Control rats received saline. Beginning 24 hr after injections, body weights and food and water consumption were measured at 24 hr intervals. The 1 and 2 mg/kg DFP-treated group maintained these parameters at levels equal to those of the controls. The other DFP-treatment groups showed significant depressions in body weights and in food and water consumption, but these groups recovered 48 and 72 hrs after DFP administration of 3 mg/kg or 4 mg/kg, respectively. Daily injections of 2, 3 or 4 mg/kg of DFP, s.c., caused significant depressions of all three parameters, with only 75% of the 2 mg/kg group showing recovery over the 14 day treatment period. Of the 2 mg/kg group, 25% died following the 6th injection, 100% of the 3 mg/kg group were dead following the 4th injection and 100% of the 4 mg/kg group were dead following the 3rd injection. Prior to deaths in all DFP-treatment groups, the decreases in body weights and in food and water consumption were progressive and dose-dependent. The data show dose-dependency of general toxicity during acute and subacute exposure to DFP and of tolerance during subacute exposure.

Animals↗
PubMed1982

Insulin prevention of impaired renal calcium transport in alloxan-diabetic rats.

The uptake of calcium-45 was measured in slices of kidney cortex from rats with alloxan-diabetes of increasing durations. Slices from untreated diabetic rats had significantly lower slice-to-medium ratios for calcium than did slices from control rats, reflecting decreased uptake of calcium by cortical slices from diabetic rats. Institution of daily insulin therapy immediately upon confirmation of diabetes prevented this depression of calcium uptake, even though the insulin therapy was insufficient to control blood glucose levels. After four weeks of untreated alloxan-diabetes, insulin therapy did not return calcium uptake by kidney cortex slices to control levels.

Animals↗
PubMed1982

Chlordecone-induced alterations in content and subcellular distribution of calcium in mouse brain.

The neurotoxic insecticide chlordecone was administered orally to "young" (4-6 wk old) and "old" (6 mo old) mice in a dose of 25 mg/kg X d in 10 ml/kg corn oil. Age-matched control mice received 10 ml/kg X d corn oil. The acute (24 h after a single dose) and subchronic (24 h after 8 daily doses) effects of chlordecone on content and subcellular distribution of Ca in the brain were studied. Significant differences in Ca content and subcellular distribution were found between the young and old control mice. Whole brains of old mice had significantly greater amounts of total brain Ca, protein-bound Ca, and mitochondrial Ca than did those of young mice, but significantly less nuclear and cytosol Ca. Acute exposure to chlordecone (no signs of neurotoxicity) increased significantly total brain, protein-bound, nuclear, mitochondrial, and myelin Ca in brains from young mice. However, under the same chlordecone exposure conditions, old mice had significantly decreased total brain, protein-bound, and mitochondrial Ca with significantly increased nuclear Ca content. It is suggested that aging caused altered biochemical responses to the neurotoxic agent, at least at subtoxic doses or exposure times. When young mice received chlordecone for 8 d and were suffering severe chlordecone-induced tremors, at the times of sacrifice, their brains were found to have significantly decreased total, protein-bound, myelin, and synaptosomal Ca. Nuclear Ca was increased. The increased excitation of the central nervous system evidenced as severe tremors induced by chlordecone might be due, at least in part, to chlordecone-induced Ca deficiency in brain synaptosomes. Such Ca deficiency may decrease the Ca-dependent release of the CNS inhibitory transmitters gamma-aminobutyric acid (GABA) and dopamine.

Animals↗